An improved understanding of many neuropsychiatric disorders has been obtained by studying the synapse as a critical site in the disease process and characterizing the synaptic action of specific neurotransmitters and neuromodulators. Some of these behavioral disorders are associated with disturbances in the neural circuitry of the hypothalamic-limbic system. The hippocampus is an integral part of the limbic system, possesses receptors for a wide variety of neurotransmitters and neuropeptides, and has been well-characterized with respect to intracellular electrical events occurring after receptor activation. An extremely dense concentration of luteinizing hormone releasing hormone (LHRH) receptors are found in the pyramidal cell layer of the hippocampus. LHRH is a neuropeptide localized in specific central nervous system sites and has been implicated in the modulation of reproductive behavior. The concentration of LHRH receptors in the hippocampus is modulated by hormones associated with reproductive function. Additionally, the hippocampus is steroid sensitive, contains morphological sex differences, and is thought to play an important role in processing information to the hypothalamus. Thus, the overall goal of this five year research proposal is to establish the biochemical and electrophysiological consequences of LHRH binding to hippocampal receptors. The proposed experiments are based on our recent findings that the application of LHRH to hippocampal cells initiates a series of biological events. Electrophysiologically, LHRH induces depolarization, increases membrane input resistance, reduces accommodation and reduces the slow afterhyperpolarization. Biochemically, LHRH receptor activation stimulates Ca2+ mobilization mechanisms in hippocampal neurons. The proposed experiments are designed around four main questions (specific aims): [1] What is the specificity of the LHRH-induced electrophysiological effect and what are the structural requirements of the LHRH molecule necessary to produce an action on hippocampal cells?; [2] What second messenger system(s) is activated to mediate the effect of LHRH on hippocampal neurons?; [3] Does estrogen modulate the LHRH-induced biochemical and electrophysiological actions on hippocampal cells?; and [4] What are the membrane ion currents that underlie the LHRH-induced electrophysiological effects? Two preparations will be used in the proposed experiments: the in vitro slice and the in vitro cultured cell preparation, both derived from rat hippocampus. The techniques to be used include intracellular current- and single electrode voltage-clamp recording as well as biochemical measurements of 45Ca2+ uptake, inositol phosphate turnover and cyclic nucleotide levels in hippocampal slices. The experimental animal of choice is the laboratory rat. The proposed studies are important and relevant to mental health and neuroscience since knowledge of the underlying cellular mechanism(s) of LHRH action in the limbic system will provide valuable insight into the peptidergic regulation and modulation of extra-pituitary behaviors. It is hoped that through a better understanding of these basic regulatory schemes we can ultimately comprehend the neurobehavioral and biological role of LHRH in the hippocampus specifically and in the CNS in general.